tbuckley/cabot-search huggingface dataset:
NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis
Authors: Sonja Marinović, Maja Lenartić, Karlo Mladenić, Marko Šestan, Inga Kavazović, Ante Benić, Mia Krapić, Lukas Rindlisbacher, Maja Cokarić Brdovčak, Colin Sparano, Gioana Litscher, Tamara Turk Wensveen, Ivana Mikolašević, Dora Fučkar Čupić, Lidija Bilić-Zulle, Aleksander Steinle, Ari Waisman, Adrian Hayday, Sonia Tugues, Burkhard Becher, Bojan Polić, Felix M. Wensveen
Journal: Science Immunology (2023)

Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A + γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD.
High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure Due to COVID-19: A Multicenter Phase II Trial
Authors: Raffaele Di Fenza, Naman S. Shetty, Stefano Gianni, Vibhu Parcha, Valentina Giammatteo, Bijan Safaee Fakhr, Daniel Tornberg, Olof Wall, Piotr Harbut, Peggy S. Lai, Jonathan Z. Li, Sabrina Paganoni, Stefano Cenci, Ariel L. Mueller, Timothy T. Houle, Oluwaseun Akeju, Edward A. Bittner, Somnath Bose, Louie K. Scott, Ryan W. Carroll, Fumito Ichinose, Magnus Hedenstierna, Pankaj Arora, Lorenzo Berra, Caio C. Araujo Morais, Lauren E. Gibson, Takamitsu Ikeda, Eizo Marutani, Yusuke Miyazaki, Anna Fischbach, Lisa Traeger, Martin I. Capriles, Eduardo Diaz Delgado, Grant M. Larson, Roberta Ribeiro De Santis Santiago, Carolyn La Vita, Binglan Yu, Maurizio F. Cereda, Nattaly Greene, Paula Restrepo, James P. Flynn, James Regan, Riccardo Pinciroli, Elizabeth I. Caskey, Kimberley Hutchinson, N. Stuart Harris, Josanna Rodriguez-Lopez, Marvin G. Chang, Jacob Wideaus, Matilda Widaeus, Kambiz Shahgaldi, Karl Hagman, Garima Arora, Robert Johnson
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

The effects of high-dose inhaled nitric oxide on hypoxemia in coronavirus disease (COVID-19) acute respiratory failure are unknown.
L-arginine metabolism inhibits arthritis and inflammatory bone loss
Authors: Shan Cao, Yixuan Li, Rui Song, Xianyi Meng, Maximilian Fuchs, Chunguang Liang, Katerina Kachler, Xinyu Meng, Jinming Wen, Ursula Schlötzer-Schrehardt, Verena Taudte, Arne Gessner, Meik Kunz, Ulrike Schleicher, Mario M Zaiss, Alf Kastbom, Xiaoxiang Chen, Georg Schett, Aline Bozec
Journal: Annals of the Rheumatic Diseases (2023)

Objectives To investigate the effect of the L-arginine metabolism on arthritis and inflammation-mediated bone loss. Methods L-arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by μCT and histomorphometry. In vitro, effects of L-arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients. Results L-arginine inhibited arthritis and bone loss in all three models and directly blocked TNFα-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients. Conclusion Our study demonstrated that L-arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.
A microglial activity state biomarker panel differentiates FTD-granulin and Alzheimer’s disease patients from controls
Authors: Ida Pesämaa, Stephan A. Müller, Sophie Robinson, Alana Darcher, Dominik Paquet, Henrik Zetterberg, Stefan F. Lichtenthaler, Christian Haass
Journal: Molecular Neurodegeneration (2023)

With the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states.Using mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), genetically modified to yield the most opposite homeostatic (TREM2-knockout) and disease-associated (GRN-knockout) states, we identified microglia activity-dependent markers. Non-targeted mass spectrometry was used to identify proteomic changes in microglia and cerebrospinal fluid (CSF) of Grn- and Trem2-knockout mice. Additionally, we analyzed the proteome of GRN- and TREM2-knockout hiMGL and their conditioned media. Candidate marker proteins were tested in two independent patient cohorts, the ALLFTD cohort (GRN mutation carriers versus non-carriers), as well as the proteomic data set available from the EMIF-AD MBD study.We identified proteomic changes between the opposite activation states in mouse microglia and CSF, as well as in hiMGL cell lysates and conditioned media. For further verification, we analyzed the CSF proteome of heterozygous GRN mutation carriers suffering from frontotemporal dementia (FTD). We identified a panel of six proteins (FABP3, MDH1, GDI1, CAPG, CD44, GPNMB) as potential indicators for microglial activation. Moreover, we confirmed three of these proteins (FABP3, GDI1, MDH1) to be significantly elevated in the CSF of Alzheimer's (AD) patients. Remarkably, each of these markers differentiated amyloid-positive cases with mild cognitive impairment (MCI) from amyloid-negative individuals.The identified candidate proteins reflect microglia activity and may be relevant for monitoring the microglial response in clinical practice and clinical trials modulating microglial activity and amyloid deposition. Moreover, the finding that three of these markers differentiate amyloid-positive from amyloid-negative MCI cases in the AD cohort suggests that these proteins associate with a very early immune response to seeded amyloid. This is consistent with our previous findings in the Dominantly Inherited Alzheimer's Disease Network (DIAN) cohort, where soluble TREM2 increases as early as 21 years before symptom onset. Moreover, in mouse models for amyloidogenesis, seeding of amyloid is limited by physiologically active microglia further supporting their early protective role. The biological functions of some of our main candidates (FABP3, CD44, GPNMB) also further emphasize that lipid dysmetabolism may be a common feature of neurodegenerative disorders.
What NHS services are migrants entitled to?
Authors: Fatima B. Wurie, Claire Zhang, Yusuf Ciftci, Cherstyn Hurley, Ines Campos-Matos
Journal: BMJ (2023)

The UK has experienced a rise in net migration over recent years, with 606 000 migrants arriving in the UK in 2022. 1 But are we doing enough to support migrants to access and navigate the health system?While migrants to the UK are less likely to die from the most common causes of death compared with the rest of the population, they are more likely to die of infectious diseases when compared to UK born populations. 2Covid-19 is a recent example of this. 3 International migrants had a substantial increase in risk of death in 2020 from covid, much higher than those who were born in the UK and Ireland.The pandemic exacerbated pre-existing inequalities in the distribution of risk factors for ill health and poor healthcare access, demonstrating how over exposed and under protected these groups can be.
Gaze-probe joint guidance with multi-task learning in obstetric ultrasound scanning
Authors: Qianhui Men, Clare Teng, Lior Drukker, Aris T. Papageorghiou, J. Alison Noble
Journal: Medical Image Analysis (2023)

In this work, we exploit multi-task learning to jointly predict the two decision-making processes of gaze movement and probe manipulation that an experienced sonographer would perform in routine obstetric scanning. A multimodal guidance framework, Multimodal-GuideNet, is proposed to detect the causal relationship between a real-world ultrasound video signal, synchronized gaze, and probe motion. The association between the multi-modality inputs is learned and shared through a modality-aware spatial graph that leverages useful cross-modal dependencies. By estimating the probability distribution of probe and gaze movements in real scans, the predicted guidance signals also allow inter- and intra-sonographer variations and avoid a fixed scanning path. We validate the new multi-modality approach on three types of obstetric scanning examinations, and the result consistently outperforms single-task learning under various guidance policies. To simulate sonographer's attention on multi-structure images, we also explore multi-step estimation in gaze guidance, and its visual results show that the prediction allows multiple gaze centers that are substantially aligned with underlying anatomical structures.
Correction: Targeted degradation of ⍺-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology
Authors: Jihoon Lee, Ki Woon Sung, Eun-Jin Bae, Dabin Yoon, Dasarang Kim, Jin Saem Lee, Da-ha Park, Daniel Youngjae Park, Su Ran Mun, Soon Chul Kwon, Hye Yeon Kim, Joo-Ok Min, Seung-Jae Lee, Young Ho Suh, Yong Tae Kwon
Journal: Molecular Neurodegeneration (2023)
Correction: Non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary versus de novo AML in first complete remission: a study from the ALWP/EBMT
Authors: Arnon Nagler, Myriam Labopin, Didier Blaise, Anna Maria Raiola, Lucia Lopez Corral, Stefania Bramanti, Simona Sica, Mi Kwon, Yener Koc, Jiri Pavlu, Alexander Kulagin, Alessandro Busca, Arancha Bermúdez Rodríguez, Péter Reményi, Christoph Schmid, Eolia Brissot, Jaime Sanz, Ali Bazarbachi, Sebastian Giebel, Fabio Ciceri, Mohamad Mohty
Journal: Journal of Hematology & Oncology (2023)
Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma
Authors: Adrian Marino-Enriquez, Jan Philipp Novotny, Doga C. Gulhan, Isabella Klooster, Antuan V. Tran, Macy Kasbo, Meijun Z. Lundberg, Wen-Bin Ou, Derrick L. Tao, Daniel F. Pilco-Janeta, Victor Y. Mao, Frank T. Zenke, Brittaney A. Leeper, Prafulla C. Gokhale, Glenn S. Cowley, Laurence H. Baker, Karla V. Ballman, David E. Root, Joachim Albers, Peter J. Park, Suzanne George, Jonathan A. Fletcher
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity. Experimental Design: We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in seven mouse models. Results: Clinical targeted sequencing revealed a high burden of somatic copy-number alterations (median fraction of the genome altered =0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide short hairpin RNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory nonhomologous end joining (NHEJ) hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity. Conclusions: Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.
Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM
Authors: Michael S. Petronek, Varun Monga, Kellie L. Bodeker, Michael Kwofie, Chu-Yu Lee, Kranti A. Mapuskar, Jeffrey M. Stolwijk, Amira Zaher, Brett A. Wagner, Mark C. Smith, Sandy Vollstedt, Heather Brown, Meghan L. Chandler, Amanda C. Lorack, Jared S. Wulfekuhle, Jann N. Sarkaria, Ryan T. Flynn, Jeremy D.W. Greenlee, Matthew A. Howard, Brian J. Smith, Karra A. Jones, Garry R. Buettner, Joseph J. Cullen, Joel St-Aubin, John M. Buatti, Vincent A. Magnotta, Douglas R. Spitz, Bryan G. Allen
Journal: Clinical Cancer Research (2023)

Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans.
Comparative Genomic Analysis and Clinical Outcomes of<i>BRAF</i>-mutated Advanced Biliary Tract Cancers
Authors: Tin-Yun Tang, Federico Nichetti, Ben Kaplan, Sara Lonardi, Filippo Pietrantonio, Lisa Salvatore, Caterina Vivaldi, Lorenza Rimassa, Filippo de Braud, Mario Domenico Rizzato, Dean Pavlick, Randy Chu, Anaemy Danner De Armas, Radwa Sharaf, Ethan Sokol, Jordi Rodon Ahnert, Jeffrey S. Ross, Milind Javle, Monica Niger
Journal: Clinical Cancer Research (2023)

Abstract Purpose: BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. Experimental Design: We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a “genomic cohort” [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional “clinical cohort” of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT). Results: In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P &amp;lt; 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS. Conclusions: In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.
Development and validation of a caregiver-reported Numeric Rating Scale for measuring worst scratch/itch in patients aged 6 months to younger than 6 years with atopic dermatitis
Authors: Amy S. Paller, Elaine Siegfried, Servando E. Marron, Marci Clark, Dana DiBenedetti, Lauren Nelson, Jingdong Chao, Ashish Bansal, Chien-Chia Chuang, Zhixiao Wang
Journal: Journal of the American Academy of Dermatology (2023)
mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia
Authors: Natasha Malik, Jodie Hay, Hassan N. B. Almuhanna, Karen M. Dunn, Jamie Lees, Jennifer Cassels, Jiatian Li, Rinako Nakagawa, Owen J. Sansom, Alison M. Michie
Journal: Leukemia (2023)

Targeted deletion of Raptor, a component of mechanistic target of rapamycin complex 1 (mTORC1), reveals an essential role for mTORC1 in initiation/maintenance of leukemia in a CLL model, resulting from a failure for haemopoietic stem/progenitor cells (HSPCs) to commit to the B cell lineage. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor CLL progenitor cells (PKCα-KR-transduced HSPCs) after disease establishment revealed a reduction in CLL-like disease load and a significant increase in survival in the mice. Interestingly in an aggressive CLL-like disease model, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive disease. Rapamycin, but not ibrutinib, efficiently targeted the eEF2/eEF2K translation elongation regulatory axis, downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56 phosphorylation. mTOR inhibitor treatment of primary patient CLL cells halted proliferation, at least in part through modulation of eEF2K/eEF2 phosphorylation and expression, reduced protein synthesis and inhibited expression of MCL1, Cyclin A and Cyclin D2. Our studies highlight the importance of translation elongation as a driver of disease progression and identify inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.
Unconditional Cash Transfers and Maternal Assessments of Children's Health, Nutrition, and Sleep
Authors: Jessica F. Sperber, Lisa A. Gennetian, Emma R. Hart, Alicia Kunin-Batson, Katherine Magnuson, Greg J. Duncan, Hirokazu Yoshikawa, Nathan A. Fox, Sarah Halpern-Meekin, Kimberly G. Noble
Journal: JAMA Network Open (2023)

Importance Children experiencing poverty are more likely to experience worse health outcomes, including injury, chronic illness, worse nutrition, and poorer sleep. The extent to which poverty reduction improves these outcomes is unknown. Objective To evaluate the effect of a 3-year, monthly unconditional cash transfer on health, nutrition, sleep, and health care utilization among children experiencing poverty who were healthy at birth. Design, Setting, and Participants This longitudinal randomized clinical trial recruited 1000 mother-infant dyads between May 2018 and June 2019. Dyads were recruited from postpartum wards in 12 hospitals in 4 US cities: New York, New York; Omaha, Nebraska; New Orleans, Louisiana; and Minneapolis/St Paul, Minnesota. Eligibility criteria included an annual income less than the federal poverty line, legal age for consent, English or Spanish speaking, residing in the state of recruitment, and an infant admitted to the well-baby nursery who will be discharged to the mother’s custody. Data analysis was conducted from July 2022 to August 2023. Intervention Mothers were randomly assigned to receive either a high-cash gift ($333/mo, or $3996/y) or a low-cash gift ($20/mo, or $240/y) for the first several years of their child’s life. Main Outcomes and Measures Primary preregistered outcomes reported here include an index of child health and medical care and child sleep disturbances. Secondary preregistered outcomes reported include children’s consumption of healthy and unhealthy foods. Results A total of 1000 mother-infant dyads were enrolled, with 400 randomized to the high-cash gift group and 600 to the low-cash gift group. Participants were majority Black (42%) and Hispanic (41%); 857 mothers participated in all 3 waves of data collection. We found no statistically detectable differences between the high-cash and low-cash gift groups in maternal assessments of children’s health (effect size [ES] range, 0.01-0.08; SE range, 0.02-0.07), sleep (ES range, 0.01-0.10; SE, 0.07), or health care utilization (ES range, 0.01-0.11; SE range, 0.03-0.07). However, mothers in the high-cash gift group reported higher child consumption of fresh produce at child age 2 years, the only time point it was measured (ES, 0.17; SE, 0.07; P = .03). Conclusions and Relevance In this study, unconditional cash transfers to mothers experiencing poverty did not improve reports of their child’s health, sleep, or health care utilization. However, stable income support of this magnitude improved toddlers’ consumption of fresh produce. Healthy newborns tend to grow into healthy toddlers, and the impacts of poverty reduction on children’s health and sleep may not be fully borne out until later in life. Trial Registration ClinicalTrials.gov Identifier: NCT03593356
Functional Outcomes Among Young People With Trajectories of Persistent Childhood Psychopathology
Authors: Niamh Dooley, Brendan Kennelly, Louise Arseneault, Stanley Zammit, Rob Whelan, Olivia Mosley, Delia Cotter, Mary Clarke, David R. Cotter, Ian Kelleher, Pat McGorry, Colm Healy, Mary Cannon
Journal: JAMA Network Open (2023)

Understanding which children in the general population are at greatest risk of poor functional outcomes could improve early screening and intervention strategies.
COVID-19 Therapeutics for Nonhospitalized Patients—Updates and Future Directions
Authors: Kara W. Chew, Preeti N. Malani, Rajesh T. Gandhi
Journal: JAMA (2023)

In this Viewpoint, the authors summarize the therapeutic landscape for COVID-19, discuss who is most likely to benefit from treatment, provide an update on managing illness in immunocompromised individuals, and highlight how to improve COVID-19 treatment.